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Human Granulocytic Ehrlichiosis (HGE) is a rare infectious disease that belongs to a group of diseases known as the Human Ehrlichioses. The Ehrlichioses are infectious diseases caused by bacteria in the "Ehrlichia" family. Several forms of Human Ehrlichial infection have been identified including Human Granulocytic Ehrlichiosis (HGE), Sennetsu Fever, and Human Monocytic Ehrlichiosis (HME). Though caused by different strains of Ehrlichia bacteria, the disorders are all characterized by similar symptoms.
The symptoms of Human Granulocytic Ehrlichiosis (HGE) may include a sudden high fever, headache, muscle aches (myalgia), chills, and a general feeling of weakness and fatigue (malaise) within a week or so after initial infection. In most cases, abnormal laboratory findings may occur including an abnormally low number of circulating blood platelets (thrombocytopenia), a decrease in white blood cells (leukopenia), and an abnormal increase in the level of certain liver enzymes (hepatic transaminases). In some cases, symptoms may progress to include nausea, vomiting, cough, diarrhea, loss of appetite (anorexia), and/or confusion. If Human Granulocytic Ehrlichiosis is left untreated, life-threatening symptoms, such as kidney failure and/or respiratory problems, may develop in some cases. Human Granulocytic Ehrlichiosis is caused by a bacterium of the Ehrlichiosis family that has not yet been named. The Ehrlichial bacterium is carried and transmitted by certain ticks (vectors), such as the deer tick (Ixodes scapularis) and the American dog tick (Dermacentor variabilis).
In individuals with Human Granulocytic Ehrlichiosis (HGE), the onset of symptoms usually occurs approximately one week after an individual has been bitten by a tick carrying the Ehrlichia bacterium. The particular strain of Ehrlichia bacterium responsible for HGE has not yet been named. In almost all cases, symptoms include fever, chills, muscle pain (myalgia), a general feeling of weakness and fatigue (malaise), and/or headaches. Some affected individuals may also experience coughing, nausea, vomiting, joint pain (arthralgia), and/or confusion. In extremely rare cases, a rash may appear on the skin.
In addition, most individuals with HGE exhibit an abnormal increase in the level of certain liver enzymes (hepatic transaminases); low levels of the protein albumin in the blood (hypoalbuminemia); and/or an abnormal decrease in circulating blood platelets (thrombocytopenia), red blood cells (anemia), and/or certain granular white blood cells (granulocytopenia) that play a role in removing bacteria from the blood and destroying them.
In some severe cases, if Human Granulocytic Ehrlichiosis is left untreated, life-threatening symptoms may develop, such as respiratory insufficiency, severe gastrointestinal bleeding, kidney (renal) failure, and/or liver damage.
According to the medical literature, in rare cases, individuals with HGE may be simultaneously infected with Lyme disease, a more common bacterial disease that is transmitted by deer ticks (which are also known tick vectors for HGE). In such cases, affected individuals may experience symptoms and physical findings often associated with both HGE and Lyme disease such as headache, fever, muscle aches, weakness, joint pain (arthralgia), and/or abnormalities of liver function. They may also experience certain symptoms and findings specific to one disorder yet rarely found in the other, such as the appearance of a characteristic red skin lesion (erythema chronicum migrans), which is often associated with Lyme disease, and/or a cough, thrombocytopenia, and/or granulocytopenia, which often occur in those with HGE. According to the medical literature, it is not yet clear whether coinfection with HGE and Lyme disease may result in more serious disease than that typically associated with infection with HGE or Lyme disease alone. (For more information on Lyme disease, please see the "Related Disorders" section of this report below.)
The human ehrlichioses, including Human Granulocytic Ehrlichiosis (HGE), are caused by bacteria belonging to the "Ehrlichia" family. These bacteria are transmitted to humans through the bite of infected ticks. (The ticks serve as "vectors", the name for any organism that is infected with and later transmits a particular disease agent (e.g., bacterium or virus) to another organism, which may then become infected). Ticks that may transmit the bacterium responsible for HGE include the deer tick (Ixodes scapularis) and the American dog tick (Dermacentor variabilis).
Human Granulocytic Ehrlichiosis (HGE) is caused by a species of the ehrlichial bacterium that is genetically similar to, or identical with, the species that causes Ehrlichiosis in horses (Ehrlichia equi) as well as another strain that causes Ehrlichial infection in cattle, deer, and sheep (Ehrlichia phagocytophila).
In HGE, the Ehrlichial bacteria invade and, if untreated, eventually destroy (phagocytosis) certain white blood cells (granulocytes) that play a role in infection protection. The invading bacteria form distinctive membrane-bound bacterial aggregates (morulae) within the cytoplasm of the host cell.
Until recently, the Ehrlichioses were known primarily as veterinary disorders. However, two forms of the infection are found in humans: Human Granulocytic Ehrlichiosis (HGE) and Human Monocytic Ehrlichiosis (HME). First recognized in the United States in 1986, the human ehrlichioses are considered emerging zoonotic diseases (diseases of animals that may be transmissible to man under natural conditions), according to the Centers for Disease Control and Prevention.
National incidence rates have not been determined because of wide variability in reporting. The CDC has urged improved national surveillance for Ehrlichiosis. Meanwhile, from 1986 through 1997, 1,223 cases (742 HME, 449 HE, and 32 not ascribed to a specific agent) were reported by state health departments, according to a 1999 CDC report.
HGE has been reported more frequently from the northeastern and upper midwestern states, while HME has been reported more from the southeastern and southcentral states. The distinct geographic distributions of the human ehrlichioses may result from differences in the distribution of the different species of ticks which act as the vectors for the bacteria.
Although infection with HGE may occur at any time of the year, infection is most common during the months of June and July. In theory, this disease affects males and females in equal numbers. However, in observed cases, approximately 80 percent of affected individuals are male, while about 20 percent are female. Infection tends to occur when individuals participate in recreational or occupational activities that expose them to tick vectors.
In rare cases, individuals with HGE may be simultaneously infected with Lyme disease, an infectious disease caused by the spirochete bacterium Borrelia burgdorferi. Coinfection may occur because a percentage of deer ticks in certain geographic areas may be infected with the bacterial agents for both HGE and Lyme disease. In a suburban county of New York it was found that from 2.2% to 26% of deer ticks were coinfected with the agents for HGE and Lyme disease.
Symptoms of the following disorders may be similar to those of Human Granulocytic Ehrlichiosis (HGE). Comparisons may be useful for a differential diagnosis:
Human Monocytic Ehrlichiosis (HME), a rare infectious disease, is caused by a bacterium from the "Ehrlichia" family known as Ehrlichia chaffeensis. The invading bacteria spread through blood and lymphatic vessels and invade certain cells that play an essential role in the body's immune system (monocytes and macrophages). In individuals with HME, the onset of symptoms usually occurs about three weeks after an individual has been bitten by a tick carrying the E. chaffeensis bacterium. Symptoms may initially include fever, chills, headaches, muscle pain (myalgia), and a general feeling of weakness and fatigue (malaise). Symptoms may then progress to include nausea, vomiting, loss of appetite (anorexia), and/or weight loss. Some affected individuals may also experience coughing, diarrhea, sore throat (pharyngitis), pain in the abdominal area, and/or confusion. In many cases of HME, there is also an abnormal decrease in white blood cells (leukopenia), a low number of circulating blood platelets (thrombocytopenia), and/or an abnormal increase in the level of certain liver enzymes (hepatic transaminases). Some affected individuals may also experience inflammation of the liver (hepatitis). Most cases have occurred in the mid-Atlantic and southeastern states in the United States. (For more information on this disease, choose "Human Monocytic Ehrlichiosis" as your search term in the Rare Disease Database.)
Sennetsu Fever, a rare infectious disease that also belongs to the Human Ehrlichioses, is caused by the bacterium known as Ehrlichia sennetsu. The symptoms of Sennetsu Fever may include a sudden high fever, headache, and muscle aches (myalgia) within a few weeks after initial infection. Some affected individuals may also experience nausea, vomiting, and/or loss of appetite (anorexia). In addition, in many cases, abnormal laboratory findings may occur including a decrease in white blood cells (leukopenia) and/or an abnormal increase in the level of certain liver enzymes (hepatic transaminases). The vector (or carrier) for the E. sennetsu bacterium has not yet been determined; however, some researchers believe that infection may result from ingestion of raw fish. Reported cases of Sennetsu Fever appear to be limited to Western Japan and Malaysia. (For more information on this disease, choose "Sennetsu" as your search term in the Rare Disease Database.)
The most recently identified form of Human Ehrlichiosis has been reported in four individuals in Missouri, all of whom experienced tick exposure several days prior to symptom onset. Based upon certain specialized laboratory tests, the four individuals tested positive for Ehrlichial infection yet negative for all known human forms of the disease (e.g., HGE, HME). Further tests revealed that infection was caused by Ehrlichia ewingii, a bacterium that was previously thought only to cause Ehrlichial infection in dogs (Canine Granulocytic Ehrlichiosis). The researchers indicated that there is no evidence of direct disease transmission from dogs to humans. Rather, humans and dogs both appear to be hosts to the same tick vectors. Associated symptoms typically include fever, headache, joint and muscle pain, and a general feeling of ill health (malaise). In addition, as with other forms of Human Ehrlichiosis, abnormal laboratory findings may also be present, such as abnormally low levels of circulating platelets (thrombocytopenia) and a decrease in white blood cells (leukopenia). Three of the four individuals with this form of Ehrlichiosis had been receiving therapy with medications that suppress the activities of the immune system (immunosuppressants). It is unclear whether infection with the E. ewingii bacterium usually does not affect individuals with sufficient immune system functioning (immunocompetence) or results in mild or no apparent symptoms (asymptomatic) in such cases. Therefore, the implications of such findings are not yet understood. All individuals with this form of Human Ehrlichiosis responded to treatment with the antibiotic doxycycline. (For more information on Human Ehrlichiosis treatment, please see the "Standard Therapies" section of this report below.)
Lyme disease is an infectious disease caused by the spirochete bacterium Borrelia burgdorferi. The bacterium is carried and transmitted by deer ticks ( Ixodes scapularis), which are also a known tick vector for Human Granulocytic Ehrlichiosis (HGE). In most cases, Lyme disease is first characterized by the appearance of a red skin lesion (erythema chronicum migrans), which begins as a small elevated round spot (papule) that expands to at least five centimeters in diameter. Symptoms may then progress to include low-grade fever, chills, muscle aches (myalgia), headache, a general feeling of weakness and fatigue (malaise), and/or pain and stiffness of the large joints (infectious arthritis), especially in the knees. Such symptoms may tend to occur in recurrent cycles. In severe cases, heart muscle (myocardial) and/or neurological abnormalities may occur. Most cases of Lyme disease occur in the northeastern United States. However, cases have occurred in other areas of the U.S. as well as other countries including China, Japan, Australia, and several countries in Europe. (For more information on this disease, choose "Lyme" as your search term in the Rare Disease Database.)
Babesiosis is a group of infectious diseases caused by single-celled microorganisms (protozoa) belonging to the "Babesia" family. It is believed that the Babesia protozoa are usually carried and transmitted by ticks (vectors). Babesiosis occurs primarily in animals; however, in rare cases, Babesiosis infection may occur in humans. Certain Babesia species are known to cause Babesiosis infection in humans (i.e., Babesia microti), and the deer tick ( Ixodes scapularis) is a known vector. (Deer ticks are also a known vector for HGE.) Human Babesiosis infection may cause fever, chills, headache, nausea, vomiting, and/or muscle aches (myalgia). Additional features may include premature destruction of red blood cells (hemolytic anemia), an abnormal decrease in circulating blood platelets (thrombocytopenia) and white blood cells (leukopenia), and/or an enlarged spleen (splenomegaly). Symptoms may be mild in otherwise healthy people; in addition, some infected individuals may exhibit no symptoms (asymptomatic). However, a severe form of Babesiosis, which may be life-threatening if untreated, may occur in individuals who have had their spleens removed (splenectomized) or who have an impaired immune system. In the United States, Babesiosis is most common in the northeastern states. In rare cases, Babesiosis may occur in Europe. (For more information on this disease, choose "Babesiosis" as your search term in the Rare Disease Database.)
Rocky Mountain Spotted Fever is a rare infectious disease caused by the bacterium Rickettsia rickettsii. The bacterium is carried and transmitted by tick vectors, such as the Lone Star tick (Amblyomma americanum) and the American dog tick (Dermacentor variabilis). (The American dog tick is also a known vector for HGE.) Rocky Mountain Spotted Fever is characterized by severe headache, high fever, chills, muscle aches (myalgia), and/or confusion. In most cases, a skin rash may appear approximately two to six days after tick exposure; the rash may first appear on the palms, wrists, soles, ankles, and forearms, later spreading to the face, trunk, and lower arms and legs. Some affected individuals may also experience nausea, vomiting, and/or abdominal pain. In some cases, without early diagnosis and appropriate treatment, symptoms may become life-threatening. Rocky Mountain Spotted Fever characteristically occurs in outbreaks in various areas of the Midwestern, Eastern, and Southeastern United States. (For more information on this disease, choose "Rocky Mountain Spotted Fever" as your search term in the Rare Disease Database.)
Toxic Shock Syndrome is a rare infectious disease caused by the bacterium Staphylococcus aureus, which produces and secretes a toxic substance (enterotoxin F). The initial symptoms of Toxic Shock Syndrome may include a sudden high fever, nausea, vomiting, diarrhea, headache, sore throat (pharyngitis), and/or a characteristic skin rash that resembles a bad sunburn. Later symptoms may include confusion, abnormally low blood pressure (hypotension), and/or abnormal liver function. Without early diagnosis and appropriate treatment, life-threatening symptoms may result. Most cases of Toxic Shock Syndrome occur in menstruating females, possibly in association with prolonged use of high-absorbency tampons. However, some females who have not used tampons and some males have been affected by the disorder. (For more information on this disease, choose "Toxic Shock" as your search term in the Rare Disease Database.)
There are other infectious disorders that may be characterized by sudden high fever (febrile disorders), headache, myalgia, nausea, vomiting, thrombocytopenia, leukopenia, and/or other symptoms associated with HGE. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
Human Granulocytic Ehrlichiosis (HGE) may be diagnosed based upon a thorough clinical evaluation, characteristic findings, and specialized laboratory tests.
Recently, a test developed at the Yale University School of Medicine and Connecticut Agricultural Experiment Station has been shown to be an appropriate diagnostic tool. It employs recombinant HE-44 antigen used in an ELISA (a type of enzyme immunoassay). When a team of scientists evaluated this method of diagnosis by testing normal serum samples from healthy individuals as well as serum samples from patients known to have HEG, they found that it correctly identified 87 percent of the samples from subjects with confirmed HGE.
Blood tests may reveal findings often associated with the Human Ehrlichioses such as abnormally low levels of circulating blood platelets (thrombocytopenia), low levels of certain white blood cells (leukopenia), and/or elevated levels of certain liver enzymes (such as aspartate aminotransferase [AST] and alanine aminotransferase [ALT]). In some cases, laboratory tests may reveal abnormalities of the cerebrospinal fluid. In addition, chest X-rays may reveal abnormalities in the lungs (e.g., pulmonary infiltrates, increased fluid in the lungs).
Examination of blood smears under a microscope that uses an electron beam (electron microscopy) may reveal clusters of bacteria in membrane-bound cavities (vacuoles) within certain cells (i.e., peripheral neutrophils); however, such clusters may not be apparent early in the course of infection. In some cases, additional specialized laboratory tests may then be conducted to help determine and/or to confirm a diagnosis of a specific bacterial infection.
Specialized laboratory tests may include Indirect Immunofluorescence Assays (IFA) conducted on the fluid portion of an affected individual's blood (serum). Antibodies, which are proteins manufactured by certain white blood cells, help the body fight toxins and invading microorganisms. In Indirect Immunofluorescence Assays, human antibodies are marked with special fluorescent dyes and a microscope with ultraviolet light is used, enabling researchers to observe antibody response to certain microorganisms.
IFA testing has been used in confirming a diagnosis of all known types of Human Ehrlichial infection. The bacterium that causes Human Granulocytic Ehrlichiosis (HGE) was isolated in 1996, a discovery that may lead to improved diagnostic tests. HGE may be confirmed by IFA testing, observing antibody response to the bacterium responsible for an Ehrlichial infection in horses, E. equi, a bacterium that is almost genetically identical to the bacterium causing HGE.
Measurable diagnostic rises in antibody response to the Ehrlichia bacteria may not occur until several weeks after the onset of Human Granulocytic Ehrlichiosis. As a result, initial IFA blood serum results may be negative in some cases. Therefore, more sensitive testing techniques that can help establish early diagnosis may be used in some cases.
One such process, called Polymerase Chain Reaction (PCR), is a laboratory technique in which sequences of DNA (which contains the organism's genetic information) may be quickly and repeatedly copied. This enables close analysis of the DNA, aiding in the identification of the organism in question. PCR conducted on certain bacterial DNA sequences obtained from patients' blood samples may confirm Human Ehrlichial infection due to a particular strain of Ehrlichia. PCR has been used to establish an early diagnosis of Human Granulocytic Ehrlichiosis.
Information in the medical literature indicates that because it may be difficult to differentiate Human Ehrlichial infection, such as Human Granulocytic Ehrlichiosis, from other illnesses that are also characterized by high fever (febrile illnesses), Ehrlichiosis should be considered in any patient with high fever, thrombocytopenia, and leukopenia who has recently been exposed to ticks. If HGE is suspected, treatment should not be delayed until diagnosis has been confirmed by IFA testing, since a positive antibody response may not occur until several weeks after initial infection. Therapy should begin as soon as possible after the onset of symptoms.
In rare cases, individuals who have symptoms and physical findings associated with HGE may also demonstrate certain symptoms typically associated with Lyme disease, such as the appearance of a red skin lesion (erythema chronicum migrans). In such rare cases, coinfection with HGE and Lyme disease should be considered. According to the medical literature, coinfection with the bacterial agents for HGE and Lyme disease may be confirmed by isolating both organisms from blood specimens.
The treatment of Human Granulocytic Ehrlichiosis usually entails standard doses of tetracycline or, alternatively, doxycycline. When individuals with HGE are unable to take tetracycline antibiotics (contraindicated), chloramphenicol may be effective. In severe cases of Human Granulocytic Ehrlichiosis, hospitalization may be required. Other treatment is symptomatic and supportive.
According to the medical literature, in rare cases when affected individuals have a confirmed diagnosis of coinfection with HGE and early Lyme disease, doxycycline treatment should be considered in those who can tolerate tetracycline medications.
Individuals in geographic areas who risk exposure to tick vectors for Ehrlichial infection should consider taking certain steps to prevent infection. Such steps should include wearing long-sleeved shirts, long pants, and hats; wearing light-colored clothing to make ticks more visible; using insect repellents; and carefully checking their clothing and skin (particularly the scalp and the back of the neck) after being in fields or wooded areas.
In early 1996, researchers at the University of Minnesota isolated the bacterium that causes Human Granulocytic Ehrlichiosis (HGE). Now that researchers understand how to promote the growth of this bacteria in cell culture, they can further study the nature of the organism, potentially leading to improved diagnosis and treatment of HGE. Researchers are currently working to develop a blood test that will aid in faster, more accurate diagnosis of Human Granulocytic Ehrlichiosis.
Research on tropical and other infectious diseases such as the Human Ehrlichioses is ongoing. For more information about these disorders, please contact the World Health Organization (WHO) listed in the Resources section below.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
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Report last updated: 2010/06/17 00:00:00 GMT+0